BACKGROUND & AIMS: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. METHODS: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and 16-kilodalton AR forms in the pancreas. RESULTS: Morphologic and immunohistochemical examinations suggest that small intralobular duct and centro-acinar cells proliferate in response to AR in these mice. AR transgenic mice display increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor in cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of isolated acini in vitro comparable to the situation in vivo. CONCLUSIONS: These data suggest that AR induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.
BACKGROUND & AIMS: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. METHODS: Two independently generated transgenicmouse lines overexpress 50-, 43-, 28-, 26-, and 16-kilodalton AR forms in the pancreas. RESULTS: Morphologic and immunohistochemical examinations suggest that small intralobular duct and centro-acinar cells proliferate in response to AR in these mice. ARtransgenic mice display increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells. In contrast to TGF-alphatransgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor in cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of isolated acini in vitro comparable to the situation in vivo. CONCLUSIONS: These data suggest that AR induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.
Authors: Tamara Aleksic; Bernd Baumann; Martin Wagner; Guido Adler; Thomas Wirth; Christoph K Weber Journal: Gut Date: 2006-07-26 Impact factor: 23.059
Authors: Altaf Mohammed; Naveena B Janakiram; Qian Li; Venkateshwar Madka; Misty Ely; Stan Lightfoot; Howard Crawford; Vernon E Steele; Chinthalapally V Rao Journal: Cancer Prev Res (Phila) Date: 2010-11
Authors: Stacy A Blaine; Kevin C Ray; Kevin M Branch; Pamela S Robinson; Robert H Whitehead; Anna L Means Journal: Am J Physiol Gastrointest Liver Physiol Date: 2009-07-16 Impact factor: 4.052